ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This 6-week randomized, crossover, double blind, placebo-controlled feasibility trial assessed the effect of subcutaneous pump hydrocortisone on the quality of life, mood, functional neuroimaging, behavioral/cognitive responses, sleep and metabolism in adults with primary adrenal insufficiency (PAI) compared to standard therapy.

Comment: Adrenal glucocorticoid secretion is characterized by a complex diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of short duration hormonal pulses (1). This trial (PULSES) administered usual dose hydrocortisone subcutaneously via a pump to provide safe circadian and ultradian cortisol replacement. Current usual replacement therapy with the standard, immediate-release hydrocortisone tablets cannot mimic physiologic cortisol secretion, lacks the pre-awakening cortisol surge and ultradian rhythmicity, and leads to unwanted post dose supraphysiologic cortisol peaks (2). Subcutaneous, pulsatile hydrocortisone administration altered both neural dynamics and behavioral responses related to emotional processing, visual stimulation and resting conditions, and improved physical and mental fatigue. It is well-known that HPA dysfunction is associated with depression, as well as poor sleep, well-being, mood and cognition (3).

Subjective mood responses were associated with altered functional neuroimaging responses to external stimulation, with the different temporal patterns of plasma cortisol, impacting brain areas important for emotional encoding, such as the amygdala, insula and frontal cortical regions. Physiologic stress response is tightly connected to that of the salience network, with stress hormones likely potentiating the intra-network functional connectivity, all adaptive changes favoring proper decisions and survival (4). Irrespective of treatment, participants had significant sleep disturbances, and treatment modality had no effect on sleep quality, although improved behavior post awakening, and ease of awakening was seen on pulsatile therapy. Studies have shown variable effects on slow wave sleep and reduced REM latency in PAI, all of which potentially impact cognition and emotion, through alterations in sleep fatigue and REM sleep (5). Pulsatility also improved positive mood, while no effect was observed on either working memory or metabolic parameters over the 6-week trial. It has been suggested that glucocorticoid pulsatility constitutes a regulatory factor for processes involved in cognitive psychophysiology, including (i) self-perceived domains of well-being, (ii) daily mood oscillations, and (iii) resting state neural dynamics, independently and in the context of mood regulation (1).

There are several novel approaches to mimic circadian rhythmicity in hydrocortisone treatment, including once-daily and modified-release oral preparations. However, those also do not address the normal pulsatility of cortisol secretion. Future studies in PAI patients are needed with long duration of treatment modalities, to better characterize their neuropsychological effects. This should hopefully provide the evidence needed to improve glucocorticoid treatment regimens, reduce the morbidity of current replacement therapy and reduce the long-term neuropsychiatric comorbidities in these patients.

References: 1. Kalafatakis K, Russell GM, Ferguson SG, Grabski M, Harmer CJ, Munafo MR, et al. Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial. Psychoneuroendocrinology. 2021; 124: 105096.2. Russell G, Lightman S. The human stress response. Nat Rev Endocrinol. 2019; 15(9): 525-34.3. Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun. 2007; 21(1): 9-19.4. Paltoglou G, Stefanaki C, Chrousos GP. Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review. Curr Neuropharmacol. 2024; 22(5): 976-89.5. Henry M, Ross IL, Thomas KGF. Reduced Slow-Wave Sleep and Altered Diurnal Cortisol Rhythms in Patients with Addison’s Disease. Eur J Endocrinol. 2018; 179(5): 319-30.